Vitamin D Receptor
The vitamin D receptor (VDR or NR1|1) is a member of the classical endocrine receptor subgroup of the nuclear receptor superfamily, which also includes the retinoic acid receptor, thyroid hormone receptor, estrogen receptor, progesterone receptor, androgen receptor, mineralocorticoid receptor and the glucocorticoid receptor. The vitamin D receptor bears structural and functional similarities to other members of the superfamily, all of which are capable of binding to cis-acting elements in the promoters of their target genes to modulate gene expression in response to specific ligands.
The natural ligand for the vitamin D receptor is the vitamin D3 metabolite, 1α,25-dihydroxyvitamin D3[1,25-(OH)2D3]. Vitamin D receptor associated with its ligand forms a heterodimeric complex with the retinoid X receptor (RXR), which binds to a vitamin D specific response element (VDRE) in the regulatory region of target genes to activate gene transcription. The classical target organs of 1α,25-dihydroxyvitamin D3 are the bone, kidney, parathyroid gland and the intestine, where 1α,25-dihydroxyvitamin D3 plays a role in the maintenance of calcium and phosphate homeostasis in the body and bone calcium mobilization and mineralization for bone development.
In addition, 1α,25-dihydroxyvitamin D3 has been discovered to play a role in a diverse range of non-classical physiological functions such as parathyroid hormone synthesis and secretion, differentiation and proliferation of the skin, muscle and reproductive cells, regeneration of neuronal cells and liver cells, regulation of the immune response, secretion of insulin and reproductive organ development.
Many of these non-classical effects of 1α,25-dihydroxyvitamin D3 are believed to be mediated via interaction with a putative membrane receptor which is coupled to signal transduction pathways which produce so-called rapid responses. These include, for example, effects on MAP kinase activation, release of insulin in rat islets, activation of P13 kinases in vascular endothelial cells and the opening of Ca2+ and chloride channels.
The discovery of a wide range of physiological actions of 1α,25-dihydroxyvitamin D3 has expanded the therapeutic use of vitamin D modulators to a wide variety of diseases and disorders mediated by, or otherwise affected by the vitamin D receptor or which the vitamin D receptor activity is implicated, including without limitation, hyperproliferative skin diseases, such as psoriasis (including pustulosis palmoplantaris, acrodermatitis continua and nail psoriasis), disturbances of keratinization and keratosis, disorders of sebaceous glands such as, acne, and seborrheic dermatitis, (U.S. Pat. Nos. 4,728,643 and 5,037,816); cancer, including without limitation, breast cancer, (J. NCl 89:212-218, (1997); Lancet 1: 188-191, (1989)); colon, (Lointier et al., Anticancer Res. (7:817-822, (1987), Niendorf, et al., J. Steroid Biochem. 27:815-828 (1987), Tanaka et al., Arch. Biochem. Biophys. 276:415-423 (1990), Halline et al., Endocrinology 134:1710-1717(1994)); prostrate cancer, (Urology 46:365-369 (1994)); brain glial tumours, (Baudet et al., Cancer Lett. 100:3 (1996)); squamous cell carcinoma, (Molecular and Cellular Differentiation 3:31-50, (1995)); ovarian cancer, (U.S. Pat. Nos. 6,444,658, 6,407,082); myeloid leukemia, (Blood 74:82-93 (1989), PNAS USA 80:201-204 (1983), U.S. Pat. No. 4,391,802); osteosarcoma; myelofibrosis; melanoma; diseases of, or imbalances in, the immune system, such as host versus graft and graft versus host reaction and transplant rejection, (U.S. Pat. No. 4,749,710); autoimmune diseases, including without limitation, discoid and systemic lupus erythematosus, type I diabetes mellitus, (Mathieu et al., Diabetologia 37:552-558 (1994), U.S. Pat. No. 5,665,387); multiple sclerosis, (U.S. Pat. No. 6,479,474); chronic dermatoses of auto-immune type, e.g. scleroderma and pemphigus vulgaris, and inflammatory diseases, such as inflammatory bowel disease (U.S. Pat. No. 6,358,939), asthma, (U.S. Pat. No. 6,603,031); rheumatoid arthritis, (U.S. Pat. No. 4,743,596); as well as a number of other disease states including without limitation, cognitive impairment or senile dementia (Alzheimers disease); (U.S. Pat. No. 6,573,255), hyperparathyroidism; (U.S. Pat. No. 6,376,479) and osteoporosis (U.S. Pat. No. 6,150,346).
The therapeutic application of 1α,25-dihydroxyvitamin D3, and its analogs has been traditionally limited due to their hypercalcemic effect, i.e., the effect of elevating serum calcium, which can lead to the severe hypercalcemia leading to death. Previous efforts in the design of synthetic analogs of 1α,25-dihydroxyvitamin D3 have therefore been made to separate the desired properties of 1α,25-dihydroxyvitamin D3 from its calcemic effect, however to date efforts these have met with limited success.
Examples of synthetic 1α,25-dihydroxyvitamin D3 analogs currently approved for use in patients include calcipotriol, (Dovonex®), marketed by Bristol-Meyers Squibb) for the treatment of psoriasis, paricalcitol, (Zemplar®, marketed by Abbott Laboratories), for the treatment of renal failure, doxercalciferol, (Hectorol®, Bone Care Int.) for hyperparathyroidism and 22-oxacalcitriol (also known as maxacalcitol; Chugai Pharmaceuticals). A recent study has shown Zemplar® to be effective in combination with radiation therapy for the treatment of prostate cancer, a non-classical target of 1α,25-dihydroxyvitamin D3 (Dunlap et al., British Journal of Cancer 89:746-753 (2003)).
Other clinical drug candidates include ZK161422 and ZK15202 under development by Schering AG, RO27-2310 and RO23-7553, under development by Hoffman-La Roche and EB1089, under development by Leo Pharmaceuticals. Other 1α,25-dihydroxyvitamin D3 analogs are described in the patent literature.
Although some current analogs of 1α,25-dihydroxyvitamin D3 have shown some degree of separation between their calcium mobilization effect and their beneficial effects, there is an ongoing search for analogs that exhibit even better separation of these activities, particularly for use in treatments that require either acute of chronic dosing.
In one aspect of the current invention, a family of novel 1α,25-dihydroxyvitamin D3 mimics are disclosed. The claimed compounds and compositions include compounds that are shown to be potent in inducing vitamin D receptor activity with reduced hypercalcemic effect. These compounds are potentially suitable for the treatment of diseases and disorders related to the activity of the vitamin D receptor, including without limitation, cancer, sarcoma, myeloma, hyperproliferative skin diseases such as psoriasis, vitamin D-related metabolic diseases such as hyperparathyroidism, chronic kidney disease and osteoporosis, autoimmune diseases such as type I diabetes, rheumatoid arthritis and multiple sclerosis, autoimmune conditions such as transplant rejection and Alzheimer's disease.